“The Cause of Autism: Its Footprint Tells”

Autism Symposium-Part II

May 22, 2009

Nancy Minshew, MDProfessor Psychiatry & Neurology

University of Pittsburgh USA

1. Spontaneous Mutations: Increased rate of “de novo” copy number variations: submicroscopic deletions or duplications of DNA sequences. More common in simplex than multiplex families. Opened door to two genetic mechanisms: inherited gene mutations and spontaneous copy number mutations- instability in replication of DNA

2. Potential reversal of Neurodevelopmental Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice

The Top 10 of 2007 (cont’d.)Convergence of Clinical With Anatomic

1. Spontaneous Mutations: Increased rate of “de novo” copy number variations: submicroscopic deletions or duplications of DNA sequences. More common in simplex than multiplex families. Opened door to two genetic mechanisms: inherited gene mutations and spontaneous copy number mutations- instability in replication of DNA

2. Potential reversal of Neurodevelopmental Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice

The Top 10 of 2007 (cont’d.)

Early Brain OverGrowth Shifts ThinkingFrom Entrenched, Focal Brain Dysfunction Models

To Developmental Neurobiologic Model

Getting To A Neural Systems Perspective

Group mean HC 60-70%; megalencephaly in 15%Onset accelerated growth 9-12 months w/ 15-20% macrocephaly by 4-5 yearsGrowth decelerates and plateaus so that brain volume “normalizes” in childhood, though subset remain macrocephalic throughout lifeImportant to recognize that HC>HT is not universal in autism and HC=HT and HC<HT growth trajectories also compatible with autism

Head Growth in AutismLainhart et al. Am J Med Genet 2006, 140A:2257-2274

Major role for white matter but without accompanying long tract signs and thus the difference between acquired and devel. disordersDisturbance in connectivityIncreased white matter volume associated with dysfunction, not increased functionInter-hemispheric white matter e.g. corpus callosum not involved in the same process

Minshew & Williams, Arch Neurol 2007

Implications of Brain Volume Studies

2-45

2-43

Primary sensory & motor cortexUnimodal association cortexHeteromodal association cortexIntra- and inter-hemispheric connections

Brodman’s Map & Connectivity

First substantive abnormalities of cerebral cortexRadially oriented arrays of pyramidal neurons, interneurons, axons and dendritesSmallest radial unit of information processing; then macrocolumns and receptive fields?Bilateral abnormalities in areas 3, 4, 9, 17, 21, 22Increased #, narrower, reduced neuropil space (inhibitory neurons), neurons small

Casanova et al. Acta Neuropathol 2006; 112:287-303

Minicolumn Abnormalities in Autism:Evidence of Cortical Involvement

Autism is a dysconnectivity syndrome-both increased & decreased

connectivity.”

Superior to age-, IQ-, gender- matched controls on word & non-word decoding, spelling, vocabulary, fluency

Inferior to controls on comprehension of sentences, idioms, metaphors, stories

Language Profile in HFA

Marcel JustVlad CherkasskyTim KellerNancy Minshew

Just et al. 2004, Brain 127: 1811-1821

Cortical activation & synchronization during sentence comprehension in HFA subjects

Center for Cognitive Brain Imaging

Carnegie Mellon

Sentence reading task and comprehension probe

The player was followed by the parent

Center for Cognitive

Brain Imaging

Who was following?player parent

Brain activation during sentence comprehension

in autism In Brain, 2004

Autism group has less activation in Broca’s area• (a sentence integration area)than the control group and more in Wernicke’s area• (a word processing area)Results are consistent with poorer comprehension of complex sentences, coupled with good word reading (spelling bee champs)

Example of less synchronized activation across two areas (upper panel, participant with autism) or more synchronized (lower panel,

control participant) in comprehension task

Reliably lower functional connectivity for autism participants between pairs of key areas during sentence comprehension (red end of scale denotes lower connectivity)

Reliable differences in functional connectivity: autism group has lower functional connectivity but same rank order

Marcel JustNancy MinshewTim Keller Vlad CherkasskyRajesh Kana

Just et al., 2006 [Epub ahead of print], Cereb Cortex

Functional Underconnectivity: fMRI of the Tower of London

Two systems-level characteristics of cortical function

1. It is always a set of cortical areas, not just one area, that activates in any thinking task, identifying the

multiple neural centers involved

2. The activation is synchronized across subsets of participating areas

(Broca’s and DLPFC, in this example)

Time Synchronization implies that the areas are collaborating and communicating with each other, and are not acting as independent agents

• Technical jargon: the measure of synchronization is referred to as “functional connectivity”

Theory of MindMirror Neuron Motion Processing (Gaze & Biologic Motion)Face ProcessingEmotion ProcessingMotivation, Incentive, DisincentiveLanguage- left and right hemisphereConcept formation

Other Brain Networks Affected in ASD:Innate Specialization Disturbed

What are the brain systems involved in representing the actions and intentions of other people?

Pelphrey et al. (2003) Journal of NeuroscienceCarter & Pelphrey (2007) Social Neuroscience

pSTS Region

MT/V5

0.00%

0.20%

0.40%

0.60%

0.80%

1.00%

Autism Neurotypical

BiologicalNon-biological

0.00%

0.05%

0.10%

0.15%

0.20%

0.25%

0.30%

Autism Neurotypical

BiologicalNon-biological

pSTS Region

MT/V5

t > 5.2, p < .001

R

R

t > 5.2, p < .001

Robot Clock Mechanical HumanRobot Clock Mechanical HumanRobot Clock Mechanical HumanRobot Clock Mechanical HumanRobot Clock Mechanical HumanRobot Clock Mechanical HumanRobot Clock Mechanical HumanRobot Clock Mechanical Human

1. Spontaneous Mutations: Increased rate of “de novo” copy number variations: submicroscopic deletions or duplications of DNA sequences. More common in simplex than multiplex families. Opened door to two genetic mechanisms: inherited gene mutations and spontaneous copy number mutations- instability in replication of DNA

2. Potential reversal of Neurodevelopmental Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice

The Top 10 of 2007 (cont’d.)

At this point, clear that typical brain development results in pre-fab circuitry & systems that predispose human infant to automatically orient and prefer human contact over objects, experience emotions and perceive them in others, acquire language, make sense of the world, play with toys symbolically and with others.

Convergence Across Systems

Is autism a synapse-opathy?

Neuronal OrganizationJoseph Volpe, Neonatal Neurology, 2008

Genetic Advances

Increased rate of “de novo” copy number variations: submicroscopic deletions or duplications of DNA sequences. More common in simplex than multiplex families. instability in replication of DNA

Potential reversal of Neurodevelopmental Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice;

Proof of concept that delineating neurobiologic and genetic mechanisms would lead to treatment

1. Spontaneous Mutations: Increased rate of “de novo” copy number variations: submicroscopic deletions or duplications of DNA sequences. More common in simplex than multiplex families. Opened door to two genetic mechanisms: inherited gene mutations and spontaneous copy number mutations- instability in replication of DNA

2. Potential reversal of Neurodevelopmental Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice

The Top 10 of 2007 (cont’d.)

PTEN conditional knock-out mice display enlarged brains and social behavioral deficits: PTEN interacts with several proteins in a signaling cascade that are tied to tuberous sclerosis and neurofibromatosis. 17% of individuals with autism & macrocephaly had PTEN gene. KO mice raises rescue possibilities.

Connecting Anatomy to Genes & Back

1. Spontaneous Mutations: Increased rate of “de novo” copy number variations: submicroscopic deletions or duplications of DNA sequences. More common in simplex than multiplex families. Opened door to two genetic mechanisms: inherited gene mutations and spontaneous copy number mutations- instability in replication of DNA

2. Potential reversal of Neurodevelopmental Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice

The Top 10 of 2007 (cont’d.)

Mouse models of genes associated with autism in humans: neuroligin-3 gene mouse model: mouse has deficits in social behaviors and an increased ability for spatial learning

Discovery of rare families with SHANK3 gene mutations added further evidence to synaptic dysfunction hypothesis. Codes for synapse formation & maintenance. It also interacts with neuroligins and neurolexins.

Connecting Anatomy to Genes & Back

The role of the discovered genes has been defined at a cellular-molecular level to involve common inter- related signaling pathways that regulate development of brain connections.

Emerging concept that two much (autism) and too little (Rett) connectivity both result in brain dysfunction.

Cellular defects are discrete and disorder specific.

Next Phase of Advance:A Molecular Pathophysiology

The Loop From Clinical Syndrome to Genes is Completed: Widespread disturbance in integrative processing, neural systems development, and genes related to development of connectivity

The Footprint is Visible: A Developmental Brain Disorder of Neuronal Organization

1. Spontaneous Mutations: Increased rate of “de novo” copy number variations: submicroscopic deletions or duplications of DNA sequences. More common in simplex than multiplex families. Opened door to two genetic mechanisms: inherited gene mutations and spontaneous copy number mutations- instability in replication of DNA

2. Potential reversal of Neurodevelopmental Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice

The Top 10 of 2007 (cont’d.)

Machine learning analyses of language representation in the brain: words & concepts encoded 5 ways- 5 attributes; this enables generalization in typical brain

Analyses of fMRI in face processing disorders reveals it is not a focal brain function but a distributed brain function

So What’s Really Really New

1. Spontaneous Mutations: Increased rate of “de novo” copy number variations: submicroscopic deletions or duplications of DNA sequences. More common in simplex than multiplex families. Opened door to two genetic mechanisms: inherited gene mutations and spontaneous copy number mutations- instability in replication of DNA

2. Potential reversal of Neurodevelopmental Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice

The Top 10 of 2007 (cont’d.)

Cognitive Enhancement Therapy: 18 months, focuses on cognitive, social, and emotional function and life skillsMultidimensional information integration: training a common brain mechanism needed for a wide range of abilitiesUsing animals and related information to train face processing

So What’s Really Really New: 3 New Interventions

Implications for Intervention

Speak in sentences-think in words & or picturesBrain operates in systems, systems underconnectedLocal connections over-developedKey Qs:

Does ABA develop local connections?Can new cognitive paradigms be designed to develop systems connections? Flexibility?

Use cognition to boot strap behavior laterMilieu to ingrain automatic good societal behavior

Many non-traumatic child neurologic disorders present “out of the blue”. They are divided by age groups, gray or white matter, and then regions.A recent example at CNS meeting-,neuronal ceroid lipofucshinosis, uniformly fatal, not responsive to bone marrow transplant, thus a candidate for stem cell therapy. Three forms: neonatal, infantile, juvenile.DNA as the day to day director of life; may come with faults with different decay rates-time bombs present from birth

Clarification of Onset & Genetic For Public